Male circumcision and sexual function in men and women: a survey-based, cross-sectional study in Denmark.
One-third of the world's men are circumcised, but little is known about possible sexual consequences of male circumcision. In Denmark (~5% circumcised), we examined associations of male circumcision with a range of sexual measures in both sexes. Participants in a national health survey (n = 5552) provided information about their own (men) or their spouse's (women) circumcision status and details about their sex lives. Logistic regression-derived odds ratios (ORs) measured associations of circumcision status with sexual experiences and current difficulties with sexual desire, sexual needs fulfilment and sexual functioning. Age at first intercourse, perceived importance of a good sex life and current sexual activity differed little between circumcised and uncircumcised men or between women with circumcised and uncircumcised spouses. However, circumcised men reported more partners and were more likely to report frequent orgasm difficulties after adjustment for potential confounding factors [11 vs 4%, OR(adj) = 3.26; 95% confidence interval (CI) 1.42-7.47], and women with circumcised spouses more often reported incomplete sexual needs fulfilment (38 vs 28%, OR(adj) = 2.09; 95% CI 1.05-4.16) and frequent sexual function difficulties overall (31 vs 22%, OR(adj) = 3.26; 95% CI 1.15-9.27), notably orgasm difficulties (19 vs 14%, OR(adj) = 2.66; 95% CI 1.07-6.66) and dyspareunia (12 vs 3%, OR(adj) = 8.45; 95% CI 3.01-23.74). Findings were stable in several robustness analyses, including one restricted to non-Jews and non-Moslems. Circumcision was associated with frequent orgasm difficulties in Danish men and with a range of frequent sexual difficulties in women, notably orgasm difficulties, dyspareunia and a sense of incomplete sexual needs fulfilment. Thorough examination of these matters in areas where male circumcision is more common is warranted.


Coupled transcription and translation within nuclei of mammalian cells.
It is widely assumed that the vital processes of transcription and translation are spatially separated in eukaryotes and that no translation occurs in nuclei. We localized translation sites by incubating permeabilized mammalian cells with [3H]lysine or lysyl-transfer RNA tagged with biotin or BODIPY; although most nascent polypeptides were cytoplasmic, some were found in discrete nuclear sites known as transcription "factories." Some of this nuclear translation also depends on concurrent transcription by RNA polymerase II. This coupling is simply explained if nuclear ribosomes translate nascent transcripts as those transcripts emerge from still-engaged RNA polymerases, much as they do in bacteria.


Evaluation of Health-related Quality of Life in Paediatric Patients with Acute Lymphoblastic Leukaemia.
Health-related quality of life (HRQOL) measurement is used for assessing the impact of diseases and medical treatments on physical, psychological and social aspects of an individual's health and life. The Paediatric Quality of Life Inventory™ (PedsQL™) is a widely used instrument to measure paediatric HRQOL in children. The aim of this study is to investigate the HRQOL in paediatric patients with acute lymphoblastic leukaemia and determine the precautions for improving the quality of their life. Paediatric Quality of Life Inventory™ 4.0 was administered to 75 paediatric patients with acute lymphoblastic leukaemia, and 50 healthy age- and gender-matched children. Health-related quality of life scores were significantly lower in patients with acute lymphoblastic leukaemia than in healthy controls in this study. It is thought that determination of the psychosocial, as well as the physical impacts of the disease on the child, will positively influence the treatment given by improving the quality of life of both the child and the family.


The Genetic Architecture of Diet-Induced Hepatic Fibrosis in Mice.
We report the genetic analysis of a "humanized" hyperlipidemic mouse model for progressive nonalcoholic steatohepatitis (NASH) and fibrosis. Mice carrying transgenes for human apolipoprotein E*3-Leiden and cholesteryl ester transfer protein and fed a "Western" diet were studied on the genetic backgrounds of over 100 inbred mouse strains. The mice developed hepatic inflammation and fibrosis that was highly dependent on genetic background, with vast differences in the degree of fibrosis. Histological analysis showed features characteristic of human NASH, including macrovesicular steatosis, hepatocellular ballooning, inflammatory foci, and pericellular collagen deposition. Time course experiments indicated that while hepatic triglyceride levels increased steadily on the diet, hepatic fibrosis occurred at about 12 weeks. We found that the genetic variation predisposing to NASH and fibrosis differs markedly from that predisposing to simple steatosis, consistent with a multistep model in which distinct genetic factors are involved. Moreover, genome-wide association identified distinct genetic loci contributing to steatosis and NASH. Finally, we used hepatic expression data from the mouse panel and from 68 bariatric surgery patients with normal liver, steatosis, or NASH to identify enriched biological pathways. Conclusion: The pathways showed substantial overlap between our mouse model and the human disease.


Glutaredoxin GRXS13 plays a key role in protection against photooxidative stress in Arabidopsis.
Glutaredoxins (GRXs) belong to the antioxidant and signalling network involved in the cellular response to oxidative stress in bacterial and eukaryotic cells. In spite of the high number of GRX genes in plant genomes, the biological functions and physiological roles of most of them remain unknown. Here the functional characterization of the Arabidopsis GRXS13 gene (At1g03850), that codes for two CC-type GRX isoforms, is reported. The transcript variant coding for the GRXS13.2 isoform is predominantly expressed under basal conditions and is the isoform that is induced by photooxidative stress. Transgenic lines where the GRXS13 gene has been knocked down show increased basal levels of superoxide radicals and reduced plant growth. These lines also display reduced tolerance to methyl viologen (MeV) and high light (HL) treatments, both conditions of photooxidative stress characterized by increased production of superoxide ions. Consistently, lines overexpressing the GRXS13.2 variant show reduced MeV- and HL-induced damage. Alterations in GRXS13 expression also affect superoxide levels and the ascorbate/dehydroascorbate ratio after HL-induced stress. These results indicate that GRXS13 gene expression is critical for limiting basal and photooxidative stress-induced reactive oxygen species (ROS) production. Together, these results place GRXS13.2 as a member of the ROS-scavenging/antioxidant network that shows a particularly low functional redundancy in the Arabidopsis GRX family.


Understanding primary care diagnosis and management of sleep disturbance for people with dementia or mild cognitive impairment: a realist review protocol.
The increasingly ageing population is associated with greater numbers of people living with dementia (PLwD) and mild cognitive impairment (MCI). There are an estimated 55 million PLwD and approximately 6% of people over 60 years of age are living with MCI, with the figure rising to 25% for those aged between 80 and 84 years. Sleep disturbances are common for this population, but there is currently no standardised approach within UK primary care to manage this. Coined as a 'wicked design problem', sleep disturbances in this population are complex, with interventions supporting best management in context. The aim of this realist review is to deepen our understanding of what is considered 'sleep disturbance' in PLwD or MCI within primary care. Specifically, we endeavour to better understand how sleep disturbance is assessed, diagnosed and managed. To co-produce this protocol and review, we have recruited a stakeholder group comprising individuals with lived experience of dementia or MCI, primary healthcare staff and sleep experts. This review will be conducted in line with Pawson's five stages including the development of our initial programme theory, literature searches and the refinement of theory. The Realist and Meta-narrative Evidence Syntheses: Evolving Standards (RAMESES) quality and reporting standards will also be followed. The realist review will be an iterative process and our initial realist programme theory will be tested and refined in response to our data searches and stakeholder discussions. Ethical approval is not required for this review. We will follow the RAMESES standards to ensure we produce a complete and transparent report. Our final programme theory will help us to devise a tailored sleep management tool for primary healthcare professionals, PLwD and their carers. Our dissemination strategy will include lay summaries via email and our research website, peer-reviewed publications and social media posts. CRD42022304679.


Exploring Structural Uncertainty and Impact of Health State Utility Values on Lifetime Outcomes in Diabetes Economic Simulation Models: Findings from the Ninth Mount Hood Diabetes Quality-of-Life Challenge.
Structural uncertainty can affect model-based economic simulation estimates and study conclusions. Unfortunately, unlike parameter uncertainty, relatively little is known about its magnitude of impact on life-years (LYs) and quality-adjusted life-years (QALYs) in modeling of diabetes. We leveraged the Mount Hood Diabetes Challenge Network, a biennial conference attended by international diabetes modeling groups, to assess structural uncertainty in simulating QALYs in type 2 diabetes simulation models. Eleven type 2 diabetes simulation modeling groups participated in the 9th Mount Hood Diabetes Challenge. Modeling groups simulated 5 diabetes-related intervention profiles using predefined baseline characteristics and a standard utility value set for diabetes-related complications. LYs and QALYs were reported. Simulations were repeated using lower and upper limits of the 95% confidence intervals of utility inputs. Changes in LYs and QALYs from tested interventions were compared across models. Additional analyses were conducted postchallenge to investigate drivers of cross-model differences. Substantial cross-model variability in incremental LYs and QALYs was observed, particularly for HbA1c and body mass index (BMI) intervention profiles. For a 0.5%-point permanent HbA1c reduction, LY gains ranged from 0.050 to 0.750. For a 1-unit permanent BMI reduction, incremental QALYs varied from a small decrease in QALYs (-0.024) to an increase of 0.203. Changes in utility values of health states had a much smaller impact (to the hundredth of a decimal place) on incremental QALYs. Microsimulation models were found to generate a mean of 3.41 more LYs than cohort simulation models (P = 0.049). Variations in utility values contribute to a lesser extent than uncertainty captured as structural uncertainty. These findings reinforce the importance of assessing structural uncertainty thoroughly because the choice of model (or models) can influence study results, which can serve as evidence for resource allocation decisions.HighlightsThe findings indicate substantial cross-model variability in QALY predictions for a standardized set of simulation scenarios and is considerably larger than within model variability to alternative health state utility values (e.g., lower and upper limits of the 95% confidence intervals of utility inputs).There is a need to understand and assess structural uncertainty, as the choice of model to inform resource allocation decisions can matter more than the choice of health state utility values.


A comparative analysis of simulated and observed photosynthetic CO2 uptake in two coniferous forest canopies.
Gross canopy photosynthesis (P(g)) can be simulated with canopy models or retrieved from turbulent carbon dioxide (CO2) flux measurements above the forest canopy. We compare the two estimates and illustrate our findings with two case studies. We used the three-dimensional canopy model MAESTRA to simulate P(g) of two spruce forests differing in age and structure. Model parameter acquisition and model sensitivity to selected model parameters are described, and modeled results are compared with independent flux estimates. Despite higher photon fluxes at the site, an older German Norway spruce (Picea abies L. (Karst.)) canopy took up 25% less CO2 from the atmosphere than a young Scottish Sitka spruce (Picea sitchensis (Bong.) Carr.) plantation. The average magnitudes of P(g) and the differences between the two canopies were satisfactorily represented by the model. The main reasons for the different uptake rates were a slightly smaller quantum yield and lower absorptance of the Norway spruce stand because of a more clumped canopy structure. The model did not represent the scatter in the turbulent CO2 flux densities, which was of the same order of magnitude as the non-photosynthetically-active-radiation-induced biophysical variability in the simulated P(g). Analysis of residuals identified only small systematic differences between the modeled flux estimates and turbulent flux measurements at high vapor pressure saturation deficits. The merits and limitations of comparative analysis for quality evaluation of both methods are discussed. From this analysis, we recommend use of both parameter sets and model structure as a basis for future applications and model development.


Loss of Clcc1 results in ER stress, misfolded protein accumulation, and neurodegeneration.
Folding of transmembrane and secretory proteins occurs in the lumen of the endoplasmic reticulum (ER) before transportation to the cell surface and is monitored by the unfolded protein response (UPR) signaling pathway. The accumulation of unfolded proteins in the ER activates the UPR that restores ER homeostasis by regulating gene expression that leads to an increase in the protein-folding capacity of the ER and a decrease in the ER protein-folding load. However, prolonged UPR activity has been associated with cell death in multiple pathological conditions, including neurodegeneration. Here, we report a spontaneous recessive mouse mutation that causes progressive cerebellar granule cell death and peripheral motor axon degeneration. By positional cloning, we identify the mutation in this strain as a retrotransposon insertion in the Clcc1 gene, which encodes a putative chloride channel localized to the ER. Furthermore, we demonstrate that the C3H/HeSnJ inbred strain has late onset cerebellar degeneration due to this mutation. Interestingly, acute knockdown of Clcc1 expression in cultured cells increases sensitivity to ER stress. In agreement, GRP78, the major HSP70 family chaperone in the ER, is upregulated in Clcc1-deficient granule cells in vivo, and ubiquitinated proteins accumulate in these neurons before their degeneration. These data suggest that disruption of chloride homeostasis in the ER disrupts the protein-folding capacity of the ER, leading to eventual neuron death.


Spatially composition-modulated two-dimensional WS2xSe2(1-x) nanosheets.
Controllable synthesis of two-dimensional (2D) transition-metal dichalcogenides (TMDs) with tunable bandgaps is vital for their applications in nanophotonics, due to its efficient modulation of the physical and chemical properties of these atomic layered nanostructures. Here we report for the first time, the controllable synthesis of spatially composition-modulated WS2xSe2(1-x) nanosheets and WS2-WS2xSe2(1-x) lateral heterostructures by a developed one-step chemical vapor deposition (CVD) approach, as well as the understanding of their growth mechanism. During the growth, the composition was optically tuned along the plane of the atomic layered nanosheets through the precise control of evaporation sources. Microstructure characterization confirms the chemical identity of the composition modulated nanosheets, with S and Se contents gradually converting from the center to the edge. Local photoluminescence (PL) and Raman studies further demonstrate the position-dependent optical properties of the as-grown nanosheets, with the PL peak and Raman modes shifting in a wide range along the whole plane of the nanostructures, which are consistent with their tunable compositions and bandgaps. This demonstration of composition-modulated nanostructures provides a beneficial approach for the preparation of 2D semiconductor heterostructures and may open up a wide range of applications in nanoelectronics and optoelectronics.


A 48-month multicentric clinical investigation: implant design and survival.
This report is based on a total of 2,955 implants of 6 different designs, randomized and placed in 829 patients and followed for 48 months. Implant failure was defined as nonintegration at uncovering or removal due to mobility, persistent pain, infection, and evidence of radiographic bone loss. Failures were reported for 3 phases of treatment: implant placement to uncovering (phase 1), uncovering to loading (phase 2), and postloading (phase 3). Differences in survival were compared with Kaplan-Meier survival curves. The maxillary single tooth application resulted in 95.2% survival for the hydroxyapatite-coated grooved implants. In the maxillary completely edentulous application, survival of hydroxyapatite grooved and screw implants were considerably better compared with the titanium screw implants. The hydroxyapatite-coated cylinder had better survival than the titanium basket and screw designs in the mandibular completely edentulous application. The hydroxyapatite-coated cylinder and grooved implants in the maxillary posterior partially edentulous application had similar survival rates. The survival of the hydroxyapatite-coated cylinder exceeded that of the titanium basket in mandibular posterior partially edentulous applications. Analyses by phase of treatment indicated a pattern of early failure for nonhydroxyapatite-coated implants compared with hydroxyapatite-coated implants. The implant with the highest survival at all phases of treatment was the hydroxyapatite-coated press-fit cylinder. Two hydroxyapatite-coated implant designs performed well in the challenging posterior maxillary region.


[Curing trial of complicated oncologic pain by D-phenylalanine (author's transl)].
Aim of investigations: Very often, chronic pain treatments used for the management of terminal ill cancer patients do not prevent acute or incident pain from coming up. For twenty months D-phenylalanine (DPA), an enkephalinase inhibitor, has been investigated in order to forestall this pain. Nine caucasian patients, three males and six females, between forty-nine and seventy-eight, were selected for this trial after informed consent. They were all undergoing severe incident pains related to complications (scabies, osteoporosis, painful cough or colic, Charley-Horse, RX-necrosis of skin or mucous membranes, etc) in spite of having their chronic pain component cured: phanol-rhizotomy: two cases, neuro-adrenolysis by alcohol: four cases, Brampton mixture: three cases. They were administered DPA, 250 mg three times a day for fifteen days, followed by a ten days pause, resumption and so on. Seven patients out of nine were alleviated and they never claimed for more or other analgesics until they died. Four of them got very good ataraxia during the same time (survival mean x = 99,33 days). No side effect was reported, even in patients taking Brampton mixture. DPA seems a useful drug to prevent acute or incident pain in malignant diseases. Our data point out the consequences the enkephalinases inhibitors will take up for the cure of intractable cancer pain.


Effect of Pimobendan in Dogs with Preclinical Myxomatous Mitral Valve Disease and Cardiomegaly: The EPIC Study-A Randomized Clinical Trial.
Pimobendan is effective in treatment of dogs with congestive heart failure (CHF) secondary to myxomatous mitral valve disease (MMVD). Its effect on dogs before the onset of CHF is unknown. Administration of pimobendan (0.4-0.6 mg/kg/d in divided doses) to dogs with increased heart size secondary to preclinical MMVD, not receiving other cardiovascular medications, will delay the onset of signs of CHF, cardiac-related death, or euthanasia. 360 client-owned dogs with MMVD with left atrial-to-aortic ratio ≥1.6, normalized left ventricular internal diameter in diastole ≥1.7, and vertebral heart sum >10.5. Prospective, randomized, placebo-controlled, blinded, multicenter clinical trial. Primary outcome variable was time to a composite of the onset of CHF, cardiac-related death, or euthanasia. Median time to primary endpoint was 1228 days (95% CI: 856-NA) in the pimobendan group and 766 days (95% CI: 667-875) in the placebo group (P = .0038). Hazard ratio for the pimobendan group was 0.64 (95% CI: 0.47-0.87) compared with the placebo group. The benefit persisted after adjustment for other variables. Adverse events were not different between treatment groups. Dogs in the pimobendan group lived longer (median survival time was 1059 days (95% CI: 952-NA) in the pimobendan group and 902 days (95% CI: 747-1061) in the placebo group) (P = .012). Administration of pimobendan to dogs with MMVD and echocardiographic and radiographic evidence of cardiomegaly results in prolongation of preclinical period and is safe and well tolerated. Prolongation of preclinical period by approximately 15 months represents substantial clinical benefit.


Oral health in children and adolescents with juvenile idiopathic arthritis - a systematic review and meta-analysis.
Observational studies examining the association between oral health and juvenile idiopathic arthritis (JIA) among children and adolescents have reported inconsistent findings. The aims of this systematic review and meta-analysis were to ascertain a potential difference in oral health and oral health-related quality of life (OHRQoL) among children and adolescents with JIA and healthy peers, and to assess the association of prevalence of oral diseases/conditions, temporomandibular disorders (TMD), including temporomandibular joint (TMJ) diseases, in relation to activity and severity of JIA. Medline Ovid, Embase, CINAHL, SweMed+ and Cochrane Library were searched up to 25 November 2018. All articles published in English, German and Scandinavian languages focusing on children and adolescents with JIA and without JIA in relation to oral health measures, were considered. Two authors independently evaluated observational studies for inclusion. The study quality was assessed using modified Newcastle Ottawa Scale. Meta-analysis was performed for studies focusing on dental caries as an outcome. Nineteen articles met the inclusion criteria, covering a range of oral diseases/conditions and OHRQoL. Eighteen studies had cross-sectional design. No mean difference of dmft/DMFT indices (decayed/missed/filled teeth) was observed between the JIA - and healthy group. None of the oral health measures including dental erosive wear, enamel defects, dental maturation and OHRQoL, indicated better oral health among children and adolescents with JIA compared to healthy group. However, periodontal conditions and TMD were more predominant among children and adolescents with JIA compared to healthy peers. Based on the cross-sectional studies, periodontal diseases and TMD were found to be more frequent in children and adolescents with JIA compared to healthy peers. Furthermore, more high-quality studies with large sample size are needed before we infer any concrete conclusion regarding the association between the prevalence of oral and TMJ diseases or oral conditions in relation to activity and severity of JIA.


Inflammatory Bowel Disease-Associated Changes in the Gut: Focus on Kazan Patients.
Several studies have highlighted the role of host-microbiome interactions in the pathogenesis of inflammatory bowel disease (IBD), resulting in an increasing amount of data mainly focusing on Western patients. Because of the increasing prevalence of IBD in newly industrialized countries such as those in Asia, the Middle East, and South America, there is mounting interest in elucidating the gut microbiota of these populations. We present a comprehensive analysis of several IBD-related biomarkers and gut microbiota profiles and functions of a unique population of patients with IBD and healthy patients from Kazan (Republic of Tatarstan, Russia). Blood and fecal IBD biomarkers, serum cytokines, and fecal short-chain fatty acid (SCFA) content were profiled. Finally, fecal microbiota composition was analyzed by 16S and whole-genome shotgun sequencing. Fecal microbiota whole-genome sequencing confirmed the presence of classic IBD dysbiotic features at the phylum level, with increased abundance of Proteobacteria, Actinobacteria, and Fusobacteria and decreased abundance of Firmicutes, Bacteroidetes, and Verrucomicrobia. At the genus level, the abundance of both fermentative (SCFA-producing and hydrogen (H2)-releasing) and hydrogenotrophic (H2-consuming) microbes was affected in patients with IBD. This imbalance was confirmed by the decreased abundance of SCFA species in the feces of patients with IBD and the change in anaerobic index, which mirrors the redox status of the intestine. Our analyses highlighted how IBD-related dysbiotic microbiota-which are generally mainly linked to SCFA imbalance-may affect other important metabolic pathways, such as H2 metabolism, that are critical for host physiology and disease development.


Ultrasmall Magnetic CuFeSe2 Ternary Nanocrystals for Multimodal Imaging Guided Photothermal Therapy of Cancer.
Nanoscale ternary chalcogenides have attracted intense research interest due to their wealth of tunable properties and diverse applications in energy and environmental and biomedical fields. In this article, ultrasmall magnetic CuFeSe2 ternary nanocrystals (<5.0 nm) were fabricated in the presence of thiol-functionalized poly(methacrylic acid) by an environmentally friendly aqueous method under ambient conditions. The small band gap and the existence of intermediate bands lead to a broad NIR absorbance in the range of 500-1100 nm and high photothermal conversion efficiency (82%) of CuFeSe2 nanocrystals. The resultant CuFeSe2 nanocrystals show superparamagnetism and effective attenuation for X-rays. In addition, they also exhibit excellent water solubility, colloidal stability, biocompatibility, and multifunctional groups. These properties enable them to be an ideal nanotheranostic agent for multimodal imaging [e.g., photoacoustic imaging (PAI), magnetic resonance imaging (MRI), computed tomography (CT) imaging] guided photothermal therapy of cancer.


Comparing NAL-NL1 and DSL v5 in Hearing Aids Fit to Children with Severe or Profound Hearing Loss: Goodness of Fit-to-Targets, Impacts on Predicted Loudness and Speech Intelligibility.
An important goal of providing amplification to children with hearing loss is to ensure that hearing aids are adjusted to match targets of prescriptive procedures as closely as possible. The Desired Sensation Level (DSL) v5 and the National Acoustic Laboratories' prescription for nonlinear hearing aids, version 1 (NAL-NL1) procedures are widely used in fitting hearing aids to children. Little is known about hearing aid fitting outcomes for children with severe or profound hearing loss. The purpose of this study was to investigate the prescribed and measured gain of hearing aids fit according to the NAL-NL1 and the DSL v5 procedure for children with moderately severe to profound hearing loss; and to examine the impact of choice of prescription on predicted speech intelligibility and loudness. Participants were fit with Phonak Naida V SP hearing aids according to the NAL-NL1 and DSL v5 procedures. The Speech Intelligibility Index (SII) and estimated loudness were calculated using published models. The sample consisted of 16 children (30 ears) aged between 7 and 17 yr old. The measured hearing aid gains were compared with the prescribed gains at 50 (low), 65 (medium), and 80 dB SPL (high) input levels. The goodness of fit-to-targets was quantified by calculating the average root-mean-square (RMS) error of the measured gain compared with prescriptive gain targets for 0.5, 1, 2, and 4 kHz. The significance of difference between prescriptions for hearing aid gains, SII, and loudness was examined by performing analyses of variance. Correlation analyses were used to examine the relationship between measures. The DSL v5 prescribed significantly higher overall gain than the NAL-NL1 procedure for the same audiograms. For low and medium input levels, the hearing aids of all children fit with NAL-NL1 were within 5 dB RMS of prescribed targets, but 33% (10 ears) deviated from the DSL v5 targets by more than 5 dB RMS on average. For high input level, the hearing aid fittings of 60% and 43% of ears deviated by more than 5 dB RMS from targets of NAL-NL1 and DSL v5, respectively. Greater deviations from targets were associated with more severe hearing loss. On average, the SII was higher for DSL v5 than for NAL-NL1 at low input level. No significant difference in SII was found between prescriptions at medium or high input level, despite greater loudness for DSL v5 than for NAL-NL1. Although targets between 0.25 and 2 kHz were well matched for both prescriptions in commercial hearing aids, gain targets at 4 kHz were matched for NAL-NL1 only. Although the two prescriptions differ markedly in estimated loudness, they resulted in comparable predicted speech intelligibility for medium and high input levels.


Can gene expression profiling predict survival for patients with squamous cell carcinoma of the lung?
Lung cancer remains to be the leading cause of cancer death worldwide. Patients with similar lung cancer may experience quite different clinical outcomes. Reliable molecular prognostic markers are needed to characterize the disparity. In order to identify the genes responsible for the aggressiveness of squamous cell carcinoma of the lung, we applied DNA microarray technology to a case control study. Fifteen patients with surgically treated stage I squamous cell lung cancer were selected. Ten were one-to-one matched on tumour size and grade, age, gender, and smoking status; five died of lung cancer recurrence within 24 months (high-aggressive group), and five survived more than 54 months after surgery (low-aggressive group). Five additional tissues were included as test samples. Unsupervised and supervised approaches were used to explore the relationship among samples and identify differentially expressed genes. We also evaluated the gene markers' accuracy in segregating samples to their respective group. Functional gene networks for the significant genes were retrieved, and their association with survival was tested. Unsupervised clustering did not group tumours based on survival experience. At p < 0.05, 294 and 246 differentially expressed genes for matched and unmatched analysis respectively were identified between the low and high aggressive groups. Linear discriminant analysis was performed on all samples using the 27 top unique genes, and the results showed an overall accuracy rate of 80%. Tests on the association of 24 gene networks with study outcome showed that 7 were highly correlated with the survival time of the lung cancer patients. The overall gene expression pattern between the high and low aggressive squamous cell carcinomas of the lung did not differ significantly with the control of confounding factors. A small subset of genes or genes in specific pathways may be responsible for the aggressive nature of a tumour and could potentially serve as panels of prognostic markers for stage I squamous cell lung cancer.


Stabilization of influenza virus replication intermediates is dependent on the RNA-binding but not the homo-oligomerization activity of the viral nucleoprotein.
The influenza virus nucleoprotein (NP) is believed to play a central role in directing a switch from RNA genome transcription to replication by the viral RNA polymerase. However, this role has recently been disputed with the proposal of alternative regulatory mechanisms. It has been suggested that the expression of viral polymerase and NP allows genome replication by stabilization of cRNA replication intermediates and complementary ribonucleoprotein (cRNP) assembly. Here, we demonstrate that the RNA-binding activity of NP is necessary for stabilization of cRNA, whereas, surprisingly, homo-oligomerization of NP is not essential. However, both RNA binding and homo-oligomerization activities are essential for genome replication.


Cross talk between physical activity and appetite control: does physical activity stimulate appetite?
Physical activity has the potential to modulate appetite control by improving the sensitivity of the physiological satiety signalling system, by adjusting macronutrient preferences or food choices and by altering the hedonic response to food. There is evidence for all these actions. Concerning the impact of physical activity on energy balance, there exists a belief that physical activity drives up hunger and increases food intake, thereby rendering it futile as a method of weight control. There is, however, no evidence for such an immediate or automatic effect. Short (1-2 d)-term and medium (7-16 d)-term studies demonstrate that men and women can tolerate substantial negative energy balances of < or = 4 MJ energy cost/d when performing physical activity programmes. Consequently, the immediate effect of taking up exercise is weight loss (although this outcome is sometimes difficult to assess due to changes in body composition or fluid compartmentalization). However, subsequently food intake begins to increase in order to provide compensation for about 30% of the energy expended in activity. This compensation (up to 16 d) is partial and incomplete. Moreover, subjects separate into compensators and non-compensators. The exact nature of these differences in compensation and whether it is actually reflective of non-compliance with protocols is yet to be determined. Some subjects (men and women) performing activity with a cost of < or = 4 MJ/d for 14 d, show no change in daily energy intake. Conversely, it can be demonstrated that when active individuals are forced into a sedentary routine food intake does not decrease to a lower level to match the reduced energy expenditure. Consequently, this situation creates a substantial positive energy balance accompanied by weight gain. The next stage is to further characterize the compensators and non-compensators, and to identify the mechanisms (physiological or behavioural) that are responsible for the rate of compensation and its limits.


Evaluation of psychological and physiological predictors of fatigue in patients with COPD.
Fatigue in COPD impairs functional status; however there are few studies examining mechanistic pathways of this symptom. The aims of this study are to compare fatigue between COPD patients and healthy age-matched subjects, and to identify predictors of fatigue in COPD. Seventy four COPD patients, mean age 69.9 (49-87) yrs, mean (SD) % predicted FEV1 46.5 (20.0) % and FEV1/FVC ratio 0.45 (0.13) and 35 healthy subjects, mean age 67.1 (50-84) yrs completed the Multidimensional Fatigue Inventory (MFI 20). Patients' assessment included Depression (HADS), lung function, BMI, muscle strength, incremental shuttle walk test (ISWT), exercise oxygen saturation (SpO2), Borg breathlessness (CR-10) and exertion (RPE). Serum level of Interleukin 6 (IL-6) was recorded. Differences in MFI 20 between groups were examined and predictors of fatigue identified using logistic regression. Significant differences (p < 0.01) were found between the COPD and healthy subjects for all MFI 20 dimensions. There were significant differences when classified according to GOLD and dyspnoea stages for selected dimensions only. Predictors of General Fatigue were depression, muscle strength and end SpO2 (R2 = .62); of Physical Fatigue: depression, % predicted FEV1, ISWT and age (R2 = .57); Reduced Activity: % predicted FEV1, BMI and depression (R2 = .36); Reduced Motivation: RPE, depression and end SpO2 (R2 = .37) and Mental Fatigue: depression and end SpO2 (R2 = .38). All dimensions of fatigue were higher in COPD than healthy aged subjects. Predictive factors differ according to the dimension of fatigue under investigation. COPD-RF is a multi component symptom requiring further consideration.


Compact highly-nonlinear AlGaAs waveguides for efficient wavelength conversion.
We report on the efficient nonlinear optical interactions in AlGaAs strip-loaded waveguides with a wafer composition specifically designed to increase the nonlinear coefficient. We demonstrate a broad-band self-phase modulation with a nonlinear phase shift up to 6π, and four-wave mixing with a 20-nm tuning range and signal-to-idler conversion efficiency up to 10 dB. Our samples are several times shorter than similar devices used for wavelength conversion by XPM and FWM in previous reports, but the efficiency of the observed effects is similar. Our experimental studies demonstrate the high potential of AlGaAs for all-optical networks.


The relationship of childhood adversity with diurnal cortisol patterns and C-reactive protein at 60-64 years of age in the 1946 National Survey of Health and Development.
Early life adversity is increasingly prevalent and associated with greater morbidity and mortality. It is hypothesised that the link between psychosocial early life adversity and poor health in adulthood is due to abnormal hypothalamic-pituitary-adrenal (HPA) axis functioning (often measured as cortisol patterning) and inflammation (often measured via c-reactive protein (CRP)). This study aimed to investigate the relationship between early life psychosocial adversity and cortisol patterning and CRP at 60-64 years of age. The MRC National Survey of Health and Development (NSHD) was used. The analytic "cortisol sample" included 843 individuals and the "CRP sample" included 1150 individuals. Data on adversity experienced between ages 0-15 years were utilised to compose a cumulative childhood psychosocial early life adversity (ELA) score (0, 1, 2, 3+). CRP and salivary cortisol (waking, 30 min after waking, and evening) were collected at 60-64 years. Associations between the psychosocial ELA score and cortisol outcomes (cortisol awakening response (CAR), diurnal slope (DS), and evening and morning cortisol) were assessed using general linear regression. Tobit regression was used to assess the association between psychosocial ELA score and CRP. Adjustments were made for age at follow-up, sex, childhood maternal education, childhood paternal social class, childhood housing tenure, and birth weight. After testing for sex by ELA score interactions, analyses were repeated stratified by sex for the CRP sample. In fully adjusted models, individuals who experienced the highest level of childhood psychosocial adversity (3+) had a 24.63 (-41.49, -7.76) % lower waking cortisol and a 7.30 (1.49, 13.12) % lower decline in cortisol across the day compared to those with a psychosocial ELA score of zero. In females, the highest level of childhood psychosocial adversity, compared to the lowest, was associated with 32.61 (2.98, 62.25) % higher CRP at 60-64 years, which attenuated to 20.38% (-9.38, 50.14) upon adjustment for measures of early life socioeconomic position. Conversely, the association between childhood psychosocial adversity and CRP in males was null. Our results suggest that high-levels of psychosocial adversity in childhood might result in a lower morning cortisol and flatter DS in mid-to-late-adulthood. The finding that adversity was related to higher CRP in females but not males requires replication and further investigation.


Trabecular bone score (TBS) as a new complementary approach for osteoporosis evaluation in clinical practice.
Trabecular bone score (TBS) is a recently-developed analytical tool that performs novel grey-level texture measurements on lumbar spine dual X-ray absorptiometry (DXA) images, and thereby captures information relating to trabecular microarchitecture. In order for TBS to usefully add to bone mineral density (BMD) and clinical risk factors in osteoporosis risk stratification, it must be independently associated with fracture risk, readily obtainable, and ideally, present a risk which is amenable to osteoporosis treatment. This paper summarizes a review of the scientific literature performed by a Working Group of the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis. Low TBS is consistently associated with an increase in both prevalent and incident fractures that is partly independent of both clinical risk factors and areal BMD (aBMD) at the lumbar spine and proximal femur. More recently, TBS has been shown to have predictive value for fracture independent of fracture probabilities using the FRAX® algorithm. Although TBS changes with osteoporosis treatment, the magnitude is less than that of aBMD of the spine, and it is not clear how change in TBS relates to fracture risk reduction. TBS may also have a role in the assessment of fracture risk in some causes of secondary osteoporosis (e.g., diabetes, hyperparathyroidism and glucocorticoid-induced osteoporosis). In conclusion, there is a role for TBS in fracture risk assessment in combination with both aBMD and FRAX.


Glycosphingolipid depletion in PC12 cells using iminosugars protects neuronal membranes from anti-ganglioside antibody mediated injury.
Autoimmune neuropathies are frequently associated with pathogenic anti-ganglioside antibodies targeting ganglioside-rich neuronal and glial membranes. The extent of injury is determined by the concentration of membrane ganglioside and thus reduction might be expected to attenuate disease. In this study, we suppressed ganglioside biosynthesis in PC12 cells with the glucosylceramide synthase inhibitor, N-butyldeoxynojirimycin and observed reduced plasma membrane antibody binding and a major neuroprotective effect in complement-mediated lysis assays. These data demonstrate that iminosugar inhibitors, currently used to treat type 1 Gaucher disease, are also of potential value for depleting antigen and thereby suppressing tissue injury in anti-ganglioside antibody-associated neuropathy.


TGF-b superfamily cytokine MIC-1/GDF15 is a physiological appetite and body weight regulator.
The TGF-b superfamily cytokine MIC-1/GDF15 circulates in all humans and when overproduced in cancer leads to anorexia/cachexia, by direct action on brain feeding centres. In these studies we have examined the role of physiologically relevant levels of MIC-1/GDF15 in the regulation of appetite, body weight and basal metabolic rate. MIC-1/GDF15 gene knockout mice (MIC-1(-/-)) weighed more and had increased adiposity, which was associated with increased spontaneous food intake. Female MIC-1(-/-) mice exhibited some additional alterations in reduced basal energy expenditure and physical activity, possibly owing to the associated decrease in total lean mass. Further, infusion of human recombinant MIC-1/GDF15 sufficient to raise serum levels in MIC-1(-/-) mice to within the normal human range reduced body weight and food intake. Taken together, our findings suggest that MIC-1/GDF15 is involved in the physiological regulation of appetite and energy storage.


Management of tuberculous constrictive pericarditis and tuberculous pericardial effusion in Transkei: results at 10 years follow-up.
Tuberculous pericarditis is common in Transkei (Eastern Cape). Two randomized trials showed benefits at two years for prednisolone in patients with constrictive pericarditis, and open drainage plus prednisolone in patients with pericardial effusion. To see whether the advantages of prednisolone and open drainage were maintained up to 10 years. Follow-up of randomized, double-blind, placebo-controlled trials. All 383 patients (143 constriction, 240 effusion) received the same anti-tuberculosis chemotherapy. They were randomized to prednisolone or placebo for the first 11 weeks, and were followed-up over 10 years. Among the 240 with effusion, 122 were also randomized to immediate open surgical drainage of pericardial fluid versus pericardiocentesis as required. Adverse outcomes were: death from pericarditis, pericardiectomy, repeat pericardiocentesis, and subsequent open drainage. The 10-year follow-up rate was 96%. In constriction patients, adverse outcomes occurred in 19/70 (27%) prednisolone vs. 28/73 (38%) placebo (p = 0.15), deaths from pericarditis being 2 (3%) vs. 8 (11%), respectively (p = 0.098, Fisher's exact test). In effusion patients, adverse outcomes occurred in 14/27 (52%) with neither drainage nor prednisolone, vs. 4/29 (14%) drainage and prednisolone, 4/35 (11%) drainage and placebo, and 6/31 (19%) prednisolone and no drainage (p = 0.08 for interaction). Drainage eliminated the need for repeat pericardiocentesis. In the 176 with effusion and no drainage, adverse outcomes occurred in 17/88 (19%) prednisolone vs. 35/88 (40%) placebo patients (p = 0.003), with repeat pericardiocentesis 20 (23%) placebo vs. 9 (10%) prednisolone (p = 0.025). In a multivariate survival analysis (stratified by type of pericarditis), prednisolone reduced the overall death rate after adjusting for age and sex (p = 0.044), and substantially reduced the risk of death from pericarditis (p = 0.004). At 10 years, the great majority of surviving patients in all treatment groups were either fully active or out and about, even if activity was restricted. In the absence of a clear contraindication, a corticosteroid should be used in addition to antituberculosis chemotherapy in the management of patients with tuberculous pericarditis.


Trust and ambivalence in midwives' views towards women developing pelvic pain during pregnancy: a qualitative study.
The Swedish midwife plays a significant role in the antenatal care (ANC) system, and a majority of pregnant women are satisfied with their ANC. Pelvic pain during pregnancy (PP) is prevalent. The study investigated the views, perceptions and attitudes of midwives currently working in ANC regarding PP during pregnancy. The informants were ten midwives between the ages of 35 to 64 years, with a combined experience of 250 years of midwifery. In-depth interviews (n = 4) and one focus group discussion (n = 6) were conducted. The data were interpreted using a qualitative content analysis design. PP was considered a common, clinical problem that had most likely increased in prevalence in recent decades and could feature prominently in a woman's experience of pregnancy. The informants had developed a strategy for supporting pregnant women affected by PP. The pregnant woman's fear of not being believed concerning her symptoms and the risk of being regarded as a malingerer were acknowledged. Mistrust between a midwife and a woman might occur when the patient's symptoms were vague and ill defined. PP was not considered as something that complicated delivery, and women experiencing it were advised to await 'the natural course of the pregnancy'. PP was considered a common, clinical problem and the informants had developed a strategy for supporting pregnant women affected by PP. However, the woman's fear of not being believed concerning her symptoms of PP was acknowledged and mistrust might occur between a midwife and a woman if vague symptoms were reported.


Simple method to measure the interaction potential of dielectric grains in a dusty plasma.
A simple minimally perturbative method is introduced which provides the ability to experimentally measure both the radial confining potential and the interaction potential between two individual dust particles, levitated in the sheath of a radio-frequency (RF) argon discharge. In this technique, a single dust particle is dropped into the plasma sheath to interact with a second individual dust particle already situated at the system's equilibrium point, without introducing any external perturbation. The resulting data are analyzed using a method employing a polynomial fit to the particle displacement(s), X(t) , to reduce uncertainty in calculation. Employing this technique, the horizontal confinement is shown to be parabolic over a wide range of pressures and displacements from the equilibrium point. The interaction potential is also measured and shown to be well described by a screened Coulomb potential and to decrease with increasing pressure. Finally, the charge on the particle and the effective dust screening distance are calculated. It is shown for the first time experimentally that the charge on a particle in the sheath of an RF plasma decreases with increasing pressure, in agreement with theoretical predictions. The screening distance also decreases with increasing pressure as expected. This technique can be used for rapid determination of particle parameters in dusty plasma.


The immunoglobulin heavy-chain gene 3' enhancers deregulate bcl-2 promoter usage in t(14;18) lymphoma cells.
In t(14;18) lymphomas, bcl-2 is juxtaposed to the immunoglobulin heavy-chain gene (IgH), resulting in increased bcl-2 transcription and resistance to apoptosis. Regulatory elements of both the bcl-2 promoter and the IgH enhancers are believed to play a role in the increased expression of bcl-2 in t(14;18) lymphoma cells. In addition, transcription of the translocated bcl-2 allele is deregulated with activation of the normally minor bcl-2 P2 promoter. The mechanisms involved in the promoter shift from P1 to P2 are not known. We found that the murine IgH 3' enhancers increased bcl-2 P2 promoter activity in an episomal model of the translocation, and IgH enhancer region HS12 had the greatest effect. Quantitative chromatin immunoprecipitation (ChIP) assays revealed that localized histone H3 hyperacetylation of the P2 promoter was observed on the translocated allele in t(14;18) DHL-4 cells and also on the stably transfected bcl-2 promoter-IgH enhancer episomal construct. Analysis of the HS12 enhancer region revealed that a previously identified nuclear factor-kappaB (NF-kappaB) site and a previously uncharacterized downstream Cdx site, both of which are conserved in the human and murine IgH enhancers, were important for its enhancer activity and promoter activation. ChIP assays showed that C/EBPbeta bound to the HS12 Cdx site in vivo, and mutation of this site abrogated the binding of C/EBPbeta. Reduced expression of C/EBPbeta by transfection of small interfering RNA or interference with NF-kappaB activity decreased transcription from the bcl-2 promoters. These results demonstrate that the IgH 3' enhancers, particularly HS12, are important for the deregulation of bcl-2 promoter usage in t(14;18) lymphomas.


Consumer participation in nurse education: a national survey of Australian universities.
Consumers of mental health services have an important role to play in the higher education of nursing students, by facilitating understanding of the experience of mental illness and instilling a culture of consumer participation. Yet the level of consumer participation in mental health nursing programmes in Australia is not known. The aim of the present study was to scope the level and nature of involvement of consumers in mental health nursing higher education in Australia. A cross-sectional study was undertaken involving an internet survey of nurse academics who coordinate mental health nursing programmes in universities across Australia, representing 32 universities. Seventy-eight percent of preregistration and 75% of post-registration programmes report involving consumers. Programmes most commonly had one consumer (25%) and up to five. Face-to-face teaching, curriculum development, and membership-to-programme committees were the most regular types of involvement. The content was generally codeveloped by consumers and nurse academics (67.5%). The frequency of consumer involvement in the education of nursing students in Australia is surprisingly high. However, involvement is noticeably variable across types of activity (e.g. curriculum development, assessment), and tends to be minimal and ad hoc. Future research is required into the drivers of increased consumer involvement.


Teacher-reported prevalence and management of child health problems at primary school.
We explored primary school teacher-reported experiences, prevalence and management of child health and developmental problems and medication administration from one multi-ethnic urban community in England. A survey was delivered to 90 reception class teachers in 45 primary schools, and semi-structured interviews were conducted with a purposive sample of eight respondents. Fifty-six percent of teachers completed the questionnaire. Findings suggest that teachers and school staff may represent an underused resource for identifying children with developmental and health conditions and that the connections formed between schools and families could be utilized by other services by delivering interventions in schools where possible. Whilst most schools use a policy to inform the management of child health in school, some key areas such as training and documentation of medication administration may not be followed in practice. Interview findings supported and expanded on survey data by identifying barriers to collaboration between services and families.


Molnupiravir plus usual care versus usual care alone as early treatment for adults with COVID-19 at increased risk of adverse outcomes (PANORAMIC): an open-label, platform-adaptive randomised controlled trial.
The safety, effectiveness, and cost-effectiveness of molnupiravir, an oral antiviral medication for SARS-CoV-2, has not been established in vaccinated patients in the community at increased risk of morbidity and mortality from COVID-19. We aimed to establish whether the addition of molnupiravir to usual care reduced hospital admissions and deaths associated with COVID-19 in this population. PANORAMIC was a UK-based, national, multicentre, open-label, multigroup, prospective, platform adaptive randomised controlled trial. Eligible participants were aged 50 years or older-or aged 18 years or older with relevant comorbidities-and had been unwell with confirmed COVID-19 for 5 days or fewer in the community. Participants were randomly assigned (1:1) to receive 800 mg molnupiravir twice daily for 5 days plus usual care or usual care only. A secure, web-based system (Spinnaker) was used for randomisation, which was stratified by age (<50 years vs ≥50 years) and vaccination status (yes vs no). COVID-19 outcomes were tracked via a self-completed online daily diary for 28 days after randomisation. The primary outcome was all-cause hospitalisation or death within 28 days of randomisation, which was analysed using Bayesian models in all eligible participants who were randomly assigned. This trial is registered with ISRCTN, number 30448031. Between Dec 8, 2021, and April 27, 2022, 26 411 participants were randomly assigned, 12 821 to molnupiravir plus usual care, 12 962 to usual care alone, and 628 to other treatment groups (which will be reported separately). 12 529 participants from the molnupiravir plus usual care group, and 12 525 from the usual care group were included in the primary analysis population. The mean age of the population was 56·6 years (SD 12·6), and 24 290 (94%) of 25 708 participants had had at least three doses of a SARS-CoV-2 vaccine. Hospitalisations or deaths were recorded in 105 (1%) of 12 529 participants in the molnupiravir plus usual care group versus 98 (1%) of 12 525 in the usual care group (adjusted odds ratio 1·06 [95% Bayesian credible interval 0·81-1·41]; probability of superiority 0·33). There was no evidence of treatment interaction between subgroups. Serious adverse events were recorded for 50 (0·4%) of 12 774 participants in the molnupiravir plus usual care group and for 45 (0·3%) of 12 934 in the usual care group. None of these events were judged to be related to molnupiravir. Molnupiravir did not reduce the frequency of COVID-19-associated hospitalisations or death among high-risk vaccinated adults in the community. UK National Institute for Health and Care Research.


Germanium nanowire growth below the eutectic temperature.
Nanowires are conventionally assumed to grow via the vapor-liquid-solid process, in which material from the vapor is incorporated into the growing nanowire via a liquid catalyst, commonly a low-melting point eutectic alloy. However, nanowires have been observed to grow below the eutectic temperature, and the state of the catalyst remains controversial. Using in situ microscopy, we showed that, for the classic Ge/Au system, nanowire growth can occur below the eutectic temperature with either liquid or solid catalysts at the same temperature. We found, unexpectedly, that the catalyst state depends on the growth pressure and thermal history. We suggest that these phenomena may be due to kinetic enrichment of the eutectic alloy composition and expect these results to be relevant for other nanowire systems.


The response of cranial biomechanical finite element models to variations in mesh density.
Finite element (FE) models provide discrete solutions to continuous problems. Therefore, to arrive at the correct solution, it is vital to ensure that FE models contain a sufficient number of elements to fully resolve all the detail encountered in a continuum structure. Mesh convergence testing is the process of comparing successively finer meshes to identify the point of diminishing returns; where increasing resolution has marginal effects on results and further detail would become costly and unnecessary. Historically, convergence has not been considered in most CT-based biomechanical reconstructions involving complex geometries like the skull, as generating such models has been prohibitively time-consuming. To assess how mesh convergence influences results, 18 increasingly refined CT-based models of a domestic pig skull were compared to identify the point of convergence for strain and displacement, using both linear and quadratic tetrahedral elements. Not all regions of the skull converged at the same rate, and unexpectedly, areas of high strain converged faster than low-strain regions. Linear models were slightly stiffer than their quadratic counterparts, but did not converge less rapidly. As expected, insufficiently dense models underestimated strain and displacement, and failed to resolve strain "hot-spots" notable in contour plots. In addition to quantitative differences, visual assessments of such plots often inform conclusions drawn in many comparative studies, highlighting that mesh convergence should be performed on all finite element models before further analysis takes place.


Learning with sublexical information from emerging reading vocabularies in exceptionally early and normal reading development.
Predictions from theories of the processes of word reading acquisition have rarely been tested against evidence from exceptionally early readers. The theories of Ehri, Share, and Byrne, and an alternative, Knowledge Sources theory, were so tested. The former three theories postulate that full development of context-free letter sounds and awareness of phonemes are required for normal acquisition, while the claim of the alternative is that with or without such, children can use sublexical information from their emerging reading vocabularies to acquire word reading. Results from two independent samples of children aged 3-5, and 5 years, with mean word reading levels of 7 and 9 years respectively, showed underdevelopment of their context-free letter sounds and phoneme awareness, relative to their word reading levels and normal comparison samples. Despite such underdevelopment, these exceptional readers engaged in a form of phonological recoding that enabled pseudoword reading, at the level of older-age normal controls matched on word reading level. Moreover, in the 5-year-old sample further experiments showed that, relative to normal controls, they had a bias toward use of sublexical information from their reading vocabularies for phonological recoding of heterophonic pseudowords with irregular consistent spelling, and were superior in accessing word meanings independently of phonology, although only if the readers were without exposure to explicit phonics. The three theories were less satisfactory than the alternative theory in accounting for the learning of the exceptionally early readers.


Combined use of transcranial magnetic stimulation and metal electrode implants: a theoretical assessment of safety considerations.
This paper provides a theoretical assessment of the safety considerations encountered in the simultaneous use of transcranial magnetic stimulation (TMS) and neurological interventions involving implanted metallic electrodes, such as electrocorticography. Metal implants are subject to magnetic forces due to fast alternating magnetic fields produced by the TMS coil. The question of whether the mechanical movement of the implants leads to irreversible damage of brain tissue is addressed by an electromagnetic simulation which quantifies the magnitude of imposed magnetic forces. The assessment is followed by a careful mechanical analysis determining the maximum tolerable force which does not cause irreversible tissue damage. Results of this investigation provide useful information on the range of TMS stimulator output powers which can be safely used in patients having metallic implants. It is shown that conventional TMS applications can be considered safe when applied on patients with typical electrode implants as the induced stress in the brain tissue remains well below the limit of tissue damage.


Osimertinib for Patients With Non-Small-Cell Lung Cancer Harboring Uncommon EGFR Mutations: A Multicenter, Open-Label, Phase II Trial (KCSG-LU15-09).
Approximately 10% of patients with epidermal growth factor receptor (EGFR) mutation-positive non-small-cell lung cancer (NSCLC) harbor uncommon mutations. Here, we report the efficacy and safety of osimertinib in patients with NSCLC harboring uncommon EGFR mutations. This was a multicenter, single-arm, open-label, phase II study in Korea. Patients with histologically confirmed metastatic or recurrent NSCLC harboring EGFR mutations other than the exon 19 deletion, L858R and T790M mutations, and exon 20 insertion were eligible for the study. The primary end point of objective response rate was assessed every 6 weeks by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Secondary end points were progression-free survival, overall survival, duration of response, and safety. Between March 2016 and October 2017, 37 patients were enrolled. All were evaluable except one patient who withdrew consent after starting treatment. Median age was 60 years, and 22 (61%) were male. Among patients, 61% received osimertinib as first-line therapy. The mutations identified were G719X (n = 19; 53%), followed by L861Q (n = 9; 25%), S768I (n = 8; 22%), and others (n = 4; 11%). Objective response rate was 50% (18 of 36 patients; 95% CI, 33% to 67%). Median progression-free survival was 8.2 months (95% CI, 5.9 to 10.5 months), and median overall survival was not reached. Median duration of response was 11.2 months (95% CI, 7.7 to 14.7 months). Adverse events of any grade were rash (n = 11; 31%), pruritus (n = 9; 25%), decreased appetite (n = 9; 25%), diarrhea (n = 8; 22%), and dyspnea (n = 8; 22%), but all adverse events were manageable. Osimertinib demonstrated favorable activity with manageable toxicity in patients with NSCLC harboring uncommon EGFR mutations.


"Hitting the nail on the head".
Subungual malignant melanoma is a rare form of malignancy that can present at an advanced stage. We describe a case that was diagnosed after a presentation to the emergency department for a traumatic injury of the affected area. Initial presentations of malignant disease and its complications form a relatively low proportion of the caseload of emergency doctors. In this case, a patient presented after a minor injury that had failed to recover; subsequent investigation of this injury led to the diagnosis of subungual malignant melanoma in an otherwise asymptomatic patient. This is a rare case which presented in an atypical fashion, with a confounding history of minor trauma. It is presented to highlight the differential diagnosis of destructive bone lesions.


Evaluation of a bolus/infusion protocol for 11C-ABP688, a PET tracer for mGluR5.
(11)C-ABP-688 is a selective tracer for the mGluR5 receptor. Its kinetics is fast and thus favourable for an equilibrium approach to determine receptor-related parameters. The purpose of this study was to test the hypothesis that the pattern of the (11)C-ABP688 uptake using a bolus-plus-infusion (B/I) protocol at early time points corresponds to the perfusion and at a later time point to the total distribution volume. A bolus and a B/I study (1 h each) was performed in five healthy male volunteers. With the B/I protocol, early and late scans were normalized to gray matter, cerebellum and white matter. The same normalization was done on the maps of the total distribution volume (Vt) and K(1) which were calculated in the study with bolus only injection and the Logan method (Vt) and a two-tissue compartment model (K(1)). There was an excellent correlation close to the identity line between the pattern of the late uptake in the B/I study and Vt of the bolus-only study for all three normalizations. The pattern of the early uptake in the B/I study correlated well with the K(1) maps, but only when normalized to gray matter and cerebellum, not to white matter. It is demonstrated that with a B/I protocol the (11)C-ABP688 distribution in late scans reflects the pattern of the total distribution volume and is therefore a measure for the density pattern of mGluR5. The early scans following injection are related to blood flow, although not in a fully quantitative manner. The advantage of the B/I protocol is that no arterial blood sampling is required, which is advantageous in clinical studies.


Ankaferd blood stopper enhances healing after osseous grafting in patients with intrabony periodontal defects.
The aim of this clinical study were to compare the clinical efficacy of ankaferd blood stopper (ABS) when used in combination with autogenous cortical bone graft (ACB) in the treatment of intrabony periodontal defects. The study was planned as a split-mouth design. Fifteen patients with chronic periodontitis at 30 sites (six men, nine women; 42 ± 7 years) were included. Treatment sites had probing pocket depths (PPD) of ≥ 6 mm and osseous defect depths of ≥ 4 mm as radiographically assessed. Following the initial periodontal therapy, patients were randomly assigned to two treatments in contralateral areas of the dentition: ACB + ABS or ACB alone. At baseline and 6 mo after surgery, clinical parameters of plaque index, gingival index, PPD, clinical attachment level and gingival recession (GR) were recorded. The primary outcome variable was the change in clinical attachment level between baseline and 24 wk after surgery. Gingival crevicular fluid samples were collected immediately before surgery and at 2, 4, 6, 12 and 24 wk after the surgery. Gingival crevicular fluid volume was calculated and vascular endothelial growth factor levels in gingival crevicular fluid were measured. PPD decreased, clinical attachment level improved and gingival index decreased significantly in response to both modes of treatment (p < 0.05). Both treatment modalities resulted in a significant gain in radiographic bone levels compared to baseline (p < 0.05). Intergroup comparisons showed that there was a significantly higher gain in clinical attachment level in the ABS/ACB group compared to ACB group (p < 0.05) with significantly less GR (p < 0.05). Similarly, vascular endothelial growth factor concentration in gingival crevicular fluid was significantly higher in the ABS/ACB group at postoperative weeks 2 and 4 compared to the ACB group (p < 0.01). The findings suggest that ABS enhances the soft tissue healing during the periodontal defect fill by the ACB by stimulating angiogenesis and vascular endothelial cell function, prevents GR and thereby increases the clinical attachment gain.


Mitogen activated protein kinase plays a significant role in metaphase II arrest, spindle morphology, and maintenance of maturation promoting factor activity in bovine oocytes.
Mammalian oocytes are arrested at the G2/M transition of the first meiotic division from which, after reaching full size and subsequent to an LH surge, they undergo final maturation. Oocyte maturation, which involves germinal vesicle breakdown, progression through metaphase I (MI), and arrest at MII, is triggered and regulated by the coordinated action of two kinases, maturation promoting factor (MPF) and mitogen activated protein kinase (MAPK). The importance of the role of MPF in mammalian oocyte maturation is well established, while the role of MAPK, although well understood in mouse oocytes, has not been fully elucidated in oocytes of large domestic species, especially bovine oocytes. Here we show that injection of MKP-1 mRNA, which encodes a dual specificity MAPK phosphatase, into germinal vesicle stage bovine oocytes prevents the activation of MAPK during maturation. Despite the lack of MAPK activity, MKP-1-injected oocytes resume and progress through meiosis, although they are unable to arrest at MII stage and, by 22-26-hour post-maturation, exhibit decondensed pronucleus-like chromatin, a clear sign of parthenogenetic activation. MKP-1-injected bovine oocytes exhibit normal activation of MPF activity; however, by 18-hour post-maturation, MPF activity starts to decline and by 22-26 hr MPF activity is absent. MKP-1-injected oocytes also show disorganized MII spindles with poorly aligned chromosomes. In summary, our results demonstrate that in bovine oocytes MAPK activity is required for MII arrest, maintenance of MPF activity, and spindle organization.


Pre and peri-operative erythropoietin for reducing allogeneic blood transfusions in colorectal cancer surgery.
Patients with colorectal cancer are frequently anaemic and many receive allogeneic red blood cell transfusions peri and post-operatively. Transfusions are accompanied by complications and may increase the rate of recurrence in patients who have a colorectal resection. Recombinant erythropoietin was first used in dialysis patients and more recently in orthopedic surgery to facilitate autologous transfusions. Erythropoietin levels are thought to be lower in cancer patients and erythropoietin is widely used in chemotherapy to treat anaemia and improve quality of life. There may be adverse events associated with its use. Several studies have investigated erythropoietin in colorectal cancer surgery. The primary objective of this systematic review was to evaluate the efficacy of erythropoietin pre and peri-operatively, in reducing allogeneic blood transfusions in patients undergoing colorectal cancer surgery. Secondary objectives were to determine whether pre and peri-operative erythropoietin improves hematologic parameters (hemoglobin, hematocrit and reticulocyte count), quality of life, recurrence rate, and survival, without increasing the occurrence of thrombotic events and the peri-operative mortality. A literature search was performed using MEDLINE, EMBASE, abstracts from the annual meetings of the American Society of Clinical Oncology and the American Society of Colon and Rectal Surgeons until May 2008. Randomized controlled trials of erythropoietin versus placebo or no treatment/standard of care were eligible for inclusion. The study must have reported one of the primary or secondary outcomes and included anaemic patients undergoing surgery for colorectal cancer. The methodological quality of the trials was assessed using the information provided. Data were extracted and effect sizes were estimated and reported as relative risks(RR) and mean differences (MD) as appropriate. Four eligible studies were identified of ten retrieved in full. There were no statistically significant differences in the proportion of patients transfused between the erythropoietin group and control group. One of the studies showed a small difference in the median number of units transfused per patient favouring treatment. Reporting of hematologic parameters was varied however, there is no evidence for clinically significant changes. There were no significant differences in post-operative mortality or thrombotic events between groups. No included study evaluated recurrences, survival, or quality of life. Studies were of fair methodologic quality and the overall sample size was small therefore results should be interpreted with caution. There is no sufficient evidence to date to recommend pre and peri-operative erythropoietin use in colorectal cancer surgery.


Geographic assessment of cancer genome profiling studies.
Cancers arise from the accumulation of somatic genome mutations, which can be influenced by inherited genomic variants and external factors such as environmental or lifestyle-related exposure. Due to the heterogeneity of cancers, precise information about the genomic composition of germline and malignant tissues has to be correlated with morphological, clinical and extrinsic features to advance medical knowledge and treatment options. With global differences in cancer frequencies and disease types, geographic data is of importance to understand the interplay between genetic ancestry and environmental influence in cancer incidence, progression and treatment outcome. In this study, we analyzed the current landscape of oncogenomic screening publications for geographic information content and quality, to address underrepresented study populations and thereby to fill prominent gaps in our understanding of interactions between somatic variations, population genetics and environmental factors in oncogenesis. We conclude that while the use of proxy-derived geographic annotations can be useful for coarse-grained associations, the study of geo-correlated factors in cancer causation and progression will benefit from standardized geographic provenance annotations. Additionally, publication-derived geographic provenance data allowed us to highlight stark inequality in the geographies of cancer genome profiling, with a near lack of sizable studies from Africa and other large regions.


Emerging therapeutic targets in nitric oxide-dependent cardiac disease.
Nitric oxide (NO) is a free radical gas that plays paracrine/autocrine and intracrine roles in maintaining physiological cardiovascular performance. In the coronary circulation, NO mediates endothelium-dependent vasodilator responses to shear stress and agonist-induced responses to neurohumoral stimulation. In the heart, NO modulates myocardial relaxation, beta-adrenergic responses, mitochondrial respiration and substrate metabolism and excitation-contraction coupling. Endothelial dysfunction and the resulting decrease in the production, bioavailability and/or second messenger response-coupling has been implicated in coronary artery disease and complications associated with restenosis following coronary angioplasty, stent placement and coronary artery bypass grafting (CABG). However, there are a number of pathophysiological conditions (ischaemia-reperfusion, cardiac transplant rejection, myocarditis, sepsis) in which unregulated overproduction of NO and other reactive oxygen species (ROS) results in deleterious effects on cardiac function. Given the importance of NO in cardiac physiology/pathophysiology it may serve as a potential target for interventions aimed at deterring therapeutic failures of percutaneous or surgical treatments of cardiac disease as well as serving as a primary medical intervention. This review will examine the function of NO in mediating/modulating cardiac function, stressing the concept that, depending on the milieu, NO has the potential to exert either beneficial or deleterious effects on cardiac function. Moreover, this review will summarise studies in laboratory models and human studies in which NO activity, production, availability, or second messenger activation has been enhanced or inhibited in order to provide new insight for future targeting of this system for drug development.


NSP4 gene analysis of rotaviruses recovered from infected children with and without diarrhea.
The transmembrane glycoprotein NSP4 functions as a viral enterotoxin capable of inducing diarrhea in young mice. It has been suggested that NSP4 may be a key determinant of rotavirus pathogenicity and a target for vaccine development. Twenty two G1P[6] rotaviruses from babies with and without diarrhea were comparatively analyzed along with reference strains and another 22 Taiwanese human rotaviruses of G and P combination types different from the G1P[6] type. The sequence variations in the NSP4 genes were studied by direct sequencing analysis of the amplicons of reverse transcription-PCR. Two genetic groups could be identified in this analysis. While the majority of these strains were closely related to the Wa strain, the G2 viruses were closely related to the S2 strain. Furthermore, phylogenetic analysis of the NSP4 gene among the G2 rotaviruses revealed three distinct lineages associated with DS-1, S2, and E210, respectively, as has been reported previously for the VP7 gene. However, we found no apparent correlation in the deduced amino acid sequences corresponding to the proposed enterotoxic peptide region between the rotaviruses recovered from individuals with and without diarrhea. The NSP4 gene product being a pathogenic determinant may not be a generalized phenomenon.


Therapeutic potential of targeting ceramide/glucosylceramide pathway in cancer.
Sphingolipids including ceramides and its derivatives such as ceramide-1-phosphate, glucosylceramide (GlcCer), and sphingosine-1-phosphate are essential structural components of cell membranes. They now recognized as novel bioeffector molecules which control various aspects of cell growth, proliferation, apoptosis, and drug resistance. Ceramide, the central molecule of sphingolipid metabolism, generally mediates anti-proliferative responses such as inhibition of cell growth, induction of apoptosis, and/or modulation of senescence. There are two major classes of sphingolipids. One of them is glycosphingolipids which are synthesized from the hydrophobic molecule, ceramide. GlcCer, generated by glucosylceramide synthase (GCS) that transfers the glucose from UDP-glucose to ceramide, is an important glycosphingolipid metabolic intermediate. GCS regulates the balance between apoptotic ceramide and antiapoptotic GlcCer. Downregulation or inhibition of GCS results in increased apoptosis and decreased drug resistance. The mechanism underlying the drug resistance which develops with increased glucosylceramide expression is associated with P-glycoprotein. In various types of cancers, overexpression of GCS has been observed which renders GCS a good target for the treatment of cancer. This review summarizes our current knowledge on the structure and functions of glucosylceramide synthase and glucosylceramide and on the roles of glucosylceramide synthase in cancer therapy and drug resistance.


Host receptors for malaria-infected erythrocytes.
Mature trophozoites and schizonts of Plasmodium falciparum induce changes in their host erythrocyte membranes that cause infected erythrocytes to sequester by binding to capillary endothelial cells. Sequestration protects infected erythrocytes from destruction in the spleen and contributes to the pathogenesis of severe and complicated malaria. The use of in vitro parasite culture and cytoadherence assays that measure the binding of infected erythrocytes to target cells has enabled the identification of host proteins that are putative receptors to which infected erythrocytes bind. Three such receptors have been identified: the extracellular matrix protein thrombospondin, the leukocyte differentiation antigen CD36, and the intercellular adhesion molecule ICAM-1. Infected erythrocytes can bind in vitro to each of these proteins. Thrombospondin and CD36 bind to one another, but each also binds to infected erythrocytes independently. Triggering of the CD36 receptor on platelets and monocytes activates these cells in vitro, and stimulation of endothelial cells with cytokines that upregulate ICAM-1 expression can increase the binding of infected erythrocytes to endothelial cells. Studies of these and perhaps other host receptors to which infected erythrocytes bind may contribute to our understanding of pathophysiologic mechanisms in malaria.


Resistance mechanism and proteins in Aspergillus species against antifungal agents.
Aspergillus species contain pathogenic and opportunistic fungal pathogens which have the potential to cause mycosis (invasive aspergillosis) in humans. The existing antifungal drugs have limitation largely due to the development of drug-resistant isolates. To gain insight into the mechanism of action and antifungal drug resistance in Aspergillus species including biofilm formation, we have reviewed protein data of Aspergillus species during interaction with antifungals drugs (polynes, azoles and echinocandin) and phytochemicals (artemisinin, coumarin and quercetin). Our analyses provided a list of Aspergillus proteins (72 proteins) that were abundant during interaction with different antifungal agents. On the other hand, there are 26 proteins, expression level of which is affected by more than two antifungal agents, suggesting the more general response to the stress induced by the antifungal agents. Our analysis showed enzymes from cell wall remodelling, oxidative stress response and energy metabolism are the responsible factors for providing resistance against antifungal drugs in Aspergillus species and could be explored further in clinical isolates. Also, these findings have clinical importance since the effect of drug targeting different proteins can be potentiated by combination therapy. We have also discussed the opportunities ahead to study the functional role of proteins from environmental and clinical isolates of Aspergillus during its interaction with the antifungal drugs. Abbreviations: IPA: invasive pulmonary aspergillosis; IA: invasive aspergillosis; AmB: Amphotericin B; CAS: Caspofungin; VRC: Voriconazole; ITC: Itraconazole; POS: Posaconazole; ART: Artemisinin; QRT: Quercetin; CMR: Coumarin; MIC: minimal inhibitory concentration.


Mercury, lead, and zinc in baby teeth of children with autism versus controls.
This study determined the level of mercury, lead, and zinc in baby teeth of children with autism spectrum disorder (n = 15, age 6.1 +/- 2.2 yr) and typically developing children (n = 11, age = 7 +/- 1.7 yr). Children with autism had significantly (2.1-fold) higher levels of mercury but similar levels of lead and similar levels of zinc. Children with autism also had significantly higher usage of oral antibiotics during their first 12 mo of life, and possibly higher usage of oral antibiotics during their first 36 mo of life. Baby teeth are a good measure of cumulative exposure to toxic metals during fetal development and early infancy, so this study suggests that children with autism had a higher body burden of mercury during fetal/infant development. Antibiotic use is known to almost completely inhibit excretion of mercury in rats due to alteration of gut flora. Thus, higher use of oral antibiotics in the children with autism may have reduced their ability to excrete mercury, and hence may partially explain the higher level in baby teeth. Higher usage of oral antibiotics in infancy may also partially explain the high incidence of chronic gastrointestinal problems in individuals with autism.


A novel, tissue occlusive poly(ethylene glycol) hydrogel material.
The use of guided bone regeneration (GBR) techniques requires new materials meeting the needs of clinical application. Design criteria for GBR devices are biocompatibility, tissue occlusion, space provision, and clinical manageability. This study evaluates a novel biodegradable poly (ethylene glycol) (PEG) based material as tissue occlusive membrane. A subcutaneous implant model in rats was developed to test the barrier function of the PEG hydrogels over time. Fourteen rats received three membrane implants and two positive controls each. Explants were collected over a period of 7 months. Histological analysis revealed that for at least 4 months cellular infiltration in the membrane explants was lower than 1% of that of the positive controls. Therefore, the PEG based hydrogel can be regarded as tissue occlusive during this period of time. A barrier function seems to be maintained for up to 6 months. In vitro degradation studies performed with the same PEG constructs confirm the in vivo result. In conclusion, our results indicate that this novel PEG-based material has potential for use as a GBR barrier membrane.


Defining Baseline Mechanisms of Cefiderocol Resistance in the Enterobacterales.
The objective of this study was to identify putative mechanisms contributing to baseline cefiderocol resistance among carbapenem-resistant Enterobacterales (CRE). We evaluated 56 clinical CRE isolates with no previous exposure to cefiderocol. Cefiderocol and comparator agent minimum inhibitory concentrations (MICs) were determined by broth microdilution. Short-read and/or long-read whole genome sequencing was pursued. Cefiderocol nonwild type (NWT; i.e., MICs ≥4 mg/L) CRE were compared with species-specific reference genomes and with cefiderocol wild type (WT) CRE isolates to identify genes or missense mutations, potentially contributing to elevated cefiderocol MICs. A total of 14 (25%) CRE isolates met cefiderocol NWT criteria. Of the 14 NWT isolates, various β-lactamases (e.g., carbapenemases in Klebsiella pneumoniae and AmpC β-lactamases in Enterobacter cloacae complex) in combination with permeability defects were associated with a ≥ 80% positive predictive value in identifying NWT isolates. Unique mutations in the sensor kinase gene baeS were identified among NWT isolates. Cefiderocol NWT isolates were more likely to be resistant to colistin than WT isolates (29% vs. 0%). Our findings suggest that no consistent antimicrobial resistance markers contribute to baseline cefiderocol resistance in CRE isolates and, rather, cefiderocol resistance results from a combination of heterogeneous mechanisms.


First Report of Diaporthe australafricana-Caused Stem Canker and Dieback in European Hazelnut (Corylus avellana L.) in Chile.
European hazelnut (Corylus avellana L.) is an emerging crop for export, mainly in southern Chile. Stem cankers and dieback of twigs on six-year-old European hazelnut cultivar Barcelona were observed during the 2012 growing season on plantations in Panguipulli (39° 38' 37.12″ S and 72° 20' 10.87″ W), Region de Los Rios, Chile. The incidence has been variable according to the place of plantation; it was estimated at approximately 15%. Cankers were characterized by brownish-gray and brown to reddish discoloration of the vascular stem system. Hazelnut plants between 1 and 3 years old developed stem basal canker, especially at conditions of high humidity and overpopulation of weeds; at critical conditions, the affected plants generally die. Small pieces of cankered stems, selected from 10 European hazelnuts, were surface sterilized in 0.5% sodium hypochlorite for 2 min and rinsed twice in sterile distilled water prior to incubation in a humid chamber for 7 days (25 ± 2°C) to stimulate production of reproductive bodies. Black sub-epidermal perithecia with unitunicate, cylindrical-clavate, 8-spored asci (n = 20) were obtained. Ascospores were septated, hyaline, multigutulate, and slightly constricted at the septum, the average measurements were (n = 20) 13.4 ± 0.6 μm × 3.9 ± 0.2 μm. The ascospores were transferred to potato dextrose agar (PDA) and incubated for 6 days at 25°C in the dark, then hyphal tips were transferred to fresh PDA and obtained a mycelia with white, cottony, and sparse colonies. Pycnidia and smooth, unicellular, hyaline, and biguttulate alpha conidia of 6.1 to 7.2 μm × 2.8 to 3.1 μm (n = 40) were observed. Beta conidia were not observed in culture media. Mature pycnidia were also detected on hazelnut shells remaining on the soil from the previous season. The identification of the species (isolate IMI-501237) was confirmed at CABI, United Kingdom, using an internal transcribed spacer (ITS), rDNA, BLASTn analysis of the 524-bp fragment, and showed 100% identity with Diaporthe australafricana Crous & J.M. van Niekerk (accessions KC343039, KC343038). These molecular and morphological characteristics were similar that reported from Vitis vinifera (2) and Chilean blueberry (3). The sequence obtained was deposited in GenBank (Accession No. JX316218.1). A pathogenicity test was conducted with isolate IMI-501237 on four 1-year-old plants from the hazelnut cultivar Barcelona. Plants were maintained in individual bags in greenhouse conditions (14/10 h dark/light, 20°C; 70% relative humidity). Prior to inoculation, plant tissues were surface disinfected with 2% sodium hypochlorite and rinsed with sterile distilled water. Each plant was inoculated at fresh wound sites on three stems and three vegetative buds on twigs. The inoculum consisted of an agar plug with mycelia (5 mm) from the edge of an actively growing colony cultured on PDA for 6 days. Each inoculation was covered with moistened cotton and sealed with Parafilm; a control plant was inoculated in the same way with agar only. After 30 days, necrotic lesions and discolored vascular tissue were only observed on inoculated stems and twigs. Symptomatic tissues were removed and incubated on PDA. D. australafricana was consistently recovered from these tissues, satisfying Koch's postulates. The control plant showed no symptoms of the disease. D. australafricana were previously reported on Vitis vinifera in Australia and South Africa (2,4), and Vaccinium corymbosum in Chile (1,3). To our knowledge, this is the first report of Diaporthe australafricana on Corylus avellana cultivar Barcelona in worldwide. References: (1) K. Elfar et al. Plant Dis. 97:1042, 2013. (2) R. Gomes et al. Persoonia 31:1, 2013. (3) B. Latorre et al. Plant Dis. 96:5, 2012. (4) J. M. van Niekerk et al. Australas. Plant Pathol. 34:27, 2005.


Pharmacokinetics and oral bioavailability of epimedin C after oral administration of epimedin C and Herba Epimedii extract in rats.
Epimedin C, an ingredient of Herba Epimedii, has potential for treatment of cardiovascular disease and bone loss. However, there is still no sensitive analytical method to monitor epimedin C in biological samples. The goal of this study was to develop a sensitive and reliable method based on a LC-MS/MS for evaluating the pharmacokinetics of epimedin C after administration of Herba Epimedii in rat. Electrospray ionization in positive-ion mode and multiple reaction monitoring were used to identify and quantitate active components. Analytes were separated by a reverse-phase C18 column. Liquid-liquid extraction using ethyl acetate, evaporation and reconstitution was used to plasma sample preparation. Mass transition of precursor ion → product ion pairs were monitored at m/z 823.4 → 313.1 for epimedin C and m/z 237.1 → 178.9 for carbamazepine (internal standard). A calibration curve gave good linearity (r > 0.999) over the concentration range 2.5-500 ng/mL. Pharmacokinetic data demonstrated that there was rapid distribution and slow elimination after epimedin C administration (1 mg/kg, i.v.). Oral bioavailabilities of epimedin C in the pure compound and in the Herba Epimedii were around 0.58% and 0.13%, respectively. The result suggests that other herbal ingredients of Herba Epimedii may suppress the oral bioavailability of epimedin C.


11 × 5 × 9.3Gb/s WDM-CAP-PON based on optical single-side band multi-level multi-band carrier-less amplitude and phase modulation with direct detection.
We propose and demonstrate a novel WDM-CAP-PON based on optical single-side band (OSSB) multi-level multi-band carrier-less amplitude and phase modulation (MM-CAP). To enable high-speed transmission with simplified optical network unit (ONU)-side digital signal processing, 4-level 5 sub-bands CAP-16 is used here, which is generated by the digital to analogue converter (DAC). Optical single-side band (OSSB) technology is applied to extend the transmission distance against the spectrum fading effect. As a proof of concept, the experiment successfully demonstrates 11 WDM channels, 55 sub-bands, for 55 users with 9.3-Gb/s per user (after removing 7% overhead for forward error correction (FEC)) in the downstream over 40-km SMF.


Distribution and Frequency of Fusarium Species Associated with Soybean Roots in Iowa.
A 3-year survey was conducted in Iowa to characterize the distribution and frequency of species of Fusarium associated with soybean roots. Ten plants were collected from each of 40 to 57 fields each year at V2 to V5 and R3 to R4 soybean growth stages. Fusarium colonies were isolated from symptomatic and symptomless roots and identified to species based on cultural and morphological characteristics. Species identification was confirmed by amplification and sequencing of the translation elongation factor (EF1-α) gene. Fifteen species were identified; Fusarium oxysporum was isolated most frequently, accounting for more than 30% of all isolates. F. acuminatum, F. graminearum, and F. solani were also among the most frequent and widespread species. Eleven other species were recovered from few fields, accounting for less than 10% of all isolates in a given year. No consistent trends were observed in geographic distribution of species. Variability in species frequency was found between soybean growth stages. Fusarium oxysporum was recovered at higher frequency during vegetative stages (40%) than reproductive stages (22%). Conversely, species such as F. acuminatum, F. graminearum, and F. solani were recovered more often from reproductive-stage plants. No significant differences in species composition were observed among fields differing in tillage practices and row spacing.


[Nicotine as an antidepressant and regulator of sleep in subjects with depression].
Depression is a chronic and heterogeneous disorder manifesting itself by mood and sleep irregularities which ultimately can lead to suicide. Depressed individuals have a higher tendency to smoking compared to non-depressed people, and the interruption of this dependence produces even more depression. This situation may be reverted by the administration of anti-depressives and/or the use of nicotine replacement therapies. Taking into account these observations it will be explained how nicotine possibly acts in relation to two main neurotransmitters: serotonin and dopamine; and as a neuroprotective agent under a depressive condition. The effect of nicotine as a sleep regulator in depressed subjects will also be presented. AIM. To describe and discuss the evidences showing that nicotine has anti-depressive properties. In order of finding are presented in the following pages evidences showing that nicotine therapeutically can be used as an anti-depressive agent: general aspects of nicotine action (pharmacology, metabolism, nicotinic receptors), general features of depression, nicotine interactions in depressive disorders, and nicotine and the regulation of sleep. Even though the basis of the relationship 'nicotine-depression' is not clear, the suggested anti-depressive role of nicotine involves a direct action over dopaminergic and serotoninergic activity or a possible indirect action as a neuroprotective agent, events which may have therapeutic effects on the quality of sleep and enhancement of depressive symptoms.


School-Based Mindfulness Instruction: An RCT.
Many urban youth experience significant and unremitting negative stressors, including those associated with community violence, multigenerational poverty, failing educational systems, substance use, limited avenues for success, health risks, and trauma. Mindfulness instruction improves psychological functioning in a variety of adult populations; research on mindfulness for youth is promising, but has been conducted in limited populations. Informed by implementation science, we evaluated an adapted mindfulness-based stress reduction (MBSR) program to ameliorate the negative effects of stress and trauma among low-income, minority, middle school public school students. Participants were students at two Baltimore City Public Schools who were randomly assigned by grade to receive adapted MBSR or health education (Healthy Topics [HT]) programs. Self-report survey data were collected at baseline and postprogram. Deidentified data were analyzed in the aggregate, comparing MBSR and HT classes, by using regression modeling. Three hundred fifth- to eighth-grade students (mean 12.0 years) were in MBSR and HT classes and provided survey data. Participants were 50.7% female, 99.7% African American, and 99% eligible for free lunch. The groups were comparable at baseline. Postprogram, MBSR students had significantly lower levels of somatization, depression, negative affect, negative coping, rumination, self-hostility, and posttraumatic symptom severity (all Ps < .05) than HT. These findings support the hypothesis that mindfulness instruction improves psychological functioning and may ameliorate the negative effects of stress and reduce trauma-associated symptoms among vulnerable urban middle school students. Additional research is needed to explore psychological, social, and behavioral outcomes, and mechanisms of mindfulness instruction.


An update on intraoral application of colposcopy.
Colposcopy is an established technique for diagnosis in gynecology. Many premalignant and malignant lesions in these areas have discernible characteristics which can be detected using a colposcope, providing an enlarged view of the areas, allowing the colposcopist to visually distinguish normal from abnormal appearing tissue and take directed biopsies for further pathological examination. The diagnosis of a dysplastic lesion of the oral mucosa cannot be based solely on clinical findings. Therefore, histological evaluation of a representative biopsy specimen is necessary. The site for the biopsy is a subjective choice that sometimes raises doubts about its representativeness. So far, no simple and reliable method is available for selecting the most appropriate area for biopsy. Intraoral microscopy (oral application of the colposcopy technique) of mucosal lesions seems to offer advantages in selecting more representative sites for biopsy than routine clinical examination alone. The biopsy sites identified by direct oral microscopy show more advanced histologic signs than those selected by routine clinical examination. This article enlightens the application of colposcopy in diagnosis of oral premalignant lesions and malignant lesions.